This project examines molecular, electrophysiological, and in vivo interactions of ligands for sigma (s) receptors. A unifying hypothesis for binding of s ligands, including steroids, "atypical" antipsychotics, such as BMY-14802 and remoxipride, and the most selective s ligand, PRE-084, was formulated using conformational fitting and electrostatic potential calculations. All s ligands have a pharmacophore with three sites of interaction; the distances between the sites are identical for the ligands. Surface maps of electrostatic charges also are similar for all s ligands tested. Solubilized s receptors were labeled with [3H]progesterone, providing the first direct demonstration of steroid binding to the receptors. Solubilized s receptors also are modulated by certain anticonvulsant drugs. A preliminary estimation of the molecular weight of solubilized s receptors was obtained using molecular sizing chromatography. A low affinity s receptor that modulates the closing of a tonic potassium channel was demonstrated in the NCB-20 cells. The low affinity receptor may play an important physiological and pharmacological role in locomotion regulation. Studies of postmortem brains from schizophrenic patients demonstrated selective losses of s receptors in the temporal cortex and dentate nucleus of the cerebellum, suggesting a role of the s receptor in psychosis, and underscoring the importance of imaging the s receptor in vivo. Studies in mice indicated, that radiolabeled d-N-allylnormetazocine and haloperidol show potential to be developed as in vivo ligands. Studies of the binding of [125I]p-iodophenyl amanantylguanidine (PIPAG), a potential SPECT ligand, to guinea pig brain showed high affinity (0.6 nM) and a pharmacological profile and neuroanatomical distribution typical of the classical s receptor. Future work includes molecular modeling studies on other s ligands, further chemical and pharmacological studies of PRE-084, purification of s receptors, and biochemical studies on the mechanism of modulation of the low affinity s receptor on the tonic potassium channel.